Many .beta.-adrenergic blocking agents are known and used; unfortunately, however, these agents are generally subject to facile oxidative metabolic degradations. Many of the metabolites also possess significant .beta.-blocking activity and, due to their different pharmacokinetic properties, make dosing and optimization of therapy difficult. The metabolites of bufuralol, for example, have longer biological half-lives than the parent drug. Francis et al, Biomed. Mass. Spectrometry, 3, 281-285 (1976). Consequently, it is difficult to determine an adequate dose of the known .beta.-blockers for administration, especially when administering them therapeutically to patients suffering from angina pectoris, hypertension or unexpected arrhythmias during surgical operations. It would be most desirable to design .beta.-blockers which would be metabolized in a simple, predictable and controllable manner in one step to an inactive metabolite, regardless of the conditions of the patient and other drugs used. This would necessitate, however, avoiding oxidative metabolism.
The present inventor has previously devised a general soft drug approach having such objectives, one specific aspect of that approach being the inactive metabolite method. Bodor, in Proceedings of the 2nd IUPAC-IUPHAR Symposium on Strategy in Drug Research, Noordwijkerhout, J. A. Keyerling Buisman (ed.), Elsevier Scientific Publishing Company, Amsterdam, 1982; Bodor, Belgian Patent No, 889,563, Nov. 3, 1981; Chem. Abstr. 97:6651n (1982). The principles of the inactive metabolite approach are:
(1) Start the design process with a known inactive metabolite of a drug. PA1 (2) Alter the metabolite to obtain a structure that resembles (isosteric and/or isoelectronic) the starting or an analogous drug. PA1 (3) Design the structure and metabolism of the new soft compound in such a way as to yield the starting inactive metabolite in one step without going through toxic intermediates. PA1 (4) Control transport and binding properties as well as the rate of metabolism and pharmacokinetics by molecular manipulations in the activation stage. However, it is not necessary to wait for an inactive metabolite to be isolated; it may be possible to design the inactive metabolite during the general drug design process based on knowledge of structural requirements for activity as well as elimination and enzymatic cleavage. PA1 R is (1) C.sub.6 -C.sub.12 cycloalkyl-C.sub.p H.sub.2p - wherein p is 0, 1, 2 or 3; (2) C.sub.6 -C.sub.18 polycycloalkyl-C.sub.p H.sub.2p - wherein p is defined as above; (3) C.sub.6 -C.sub.18 polycycloalkenyl-C.sub.p H.sub.2p -wherein p is defined as above; (4) C.sub.6 -C.sub.12 cycloalkenyl-C.sub.p H.sub.2p wherein p is defined as above; (5) --CH.sub.2 --X--R.sub.2 wherein X is S, SO or SO.sub.2 and R.sub.2 is C.sub.1 -C.sub.7 alkyl or C.sub.3 -C.sub.12 cycloalkyl; (6) ##STR4## wherein R.sub.2 is defined as above; (7) ##STR5## wherein X is defined as above, and wherein R.sub.3 is C.sub.1 -C.sub.7 alkyl and R.sub.4 is C.sub.1 -C.sub.7 alkyl or wherein R.sub.3 and R.sub.4 taken together represent -(CH.sub.2).sub.m - wherein m is 3 or 4 and -(CH.sub.2).sub.m - is optionally substituted by one to three C.sub.1 -C.sub.7 alkyl; (8) ##STR6## wherein R.sub.5 is hydrogen or C.sub.1 -C.sub.7 alkyl and R.sub.6 is unsubstituted or substituted C.sub.1 -C.sub.7 alkyl, C.sub.3 -C.sub.12 cycloalkyl, C.sub.3 -C.sub.12 cycloalkenyl or C.sub.2 -C.sub.8 alkenyl , the substituents being selected from the group consisting of halo, C.sub.1 -C.sub.7 alkoxy, C.sub.1 -C.sub.7 alkylthio, C.sub.1 -C.sub.7 alkylsulfinyl , C.sub.1 -C.sub.7 alkylsulfonyl, ##STR7## or R.sub.6 is unsubstituted or substituted phenyl or benzyl, the substituents being selected from the group consisting of C.sub.1 -C.sub.7 alkyl , C.sub.1 -C.sub.7 alkoxy, halo, carbamoyl , C.sub.2 -C.sub.8 alkoxycarbonyl , C.sub.2 -C.sub.8 alkanoyloxy, C.sub.1 -C.sub.7 haloalkyl, mono(C.sub.1 -C.sub.7 alkyl)amino, di(C.sub.1 -C.sub.7 alkyl)amino, mono(C.sub.1 -C.sub.7 alkyl)carbamoyl , di(C.sub.1 -C.sub.7 alkyl)carbamoyl, C.sub.1 -C.sub.7 alkylthio, C.sub.1 -C.sub.7 alkylsulfinyl and C.sub.1 -C.sub.7 alkylsulfonyl; (9) ##STR8## wherein R.sub.5 and R.sub.6 are defined as above; or (10) ##STR9## wherein R.sub.5 is defined as above and R.sub.7 and R.sub.8, which can be the same or different, are each hydrogen, C.sub.1 -C.sub.7 alkyl, C.sub.3 -C.sub.12 cycloalkyl, phenyl or benzyl, or R.sub.7 and R.sub.8 are combined such that --NR.sub.7 R.sub.8 represents the residue of a saturated monocyclic secondary amine; EQU R.sub.1 is C.sub.1 -C.sub.7 alkyl;
Recently, several patent publications have described various series of short acting .beta.-adrenergic blocking compounds containing ester moieties which are structurally related to some of the compounds of the present invention. Thus, Matier U.S. Pat. No. 4,454,154, issued Jun. 12, 1984, describes a method of treating glaucoma by topical administration of selected .beta.-blockers. Lower alkyl (C.sub.1 -C.sub.10) and lower cycloalky (C.sub.3 -C.sub.5) esters are among the compounds generically disclosed by Matier, but only alkyl esters are specifically described. See also related Erhardt et al U.S. Pat. No, 4,387,103, issued Jun. 7, 1983 and American Hospital Supply Corporation's corresponding International Application No. PCT/US81/01514 published under International Publication No. WO82/01869 on Jun. 10, 1982; again, lower alkyl and lower cycloalky esters are generically disclosed, but of these only the lower alkyl esters are specifically described. The Erhardt et al patent and its PCT counterpart provide a method for the treatment or prophylaxis of cardiac disorders. A related series of short acting .beta.-blockers is described in Aktiebolaget Hassle's European Patent Application No, 81850095.1, published on Dec. 9, 1981 under European Publication No. 0041491. The Hassle application generically discloses lower alkyl (C.sub.1 -C.sub.7) and lower cycloalkyl (C.sub.3 -C.sub.6) esters, among others, but again does not specifically describe any cycloalkyl esters. Moreover, none of these publications appear to address the problem addressed by the present invention, i.e. how to design .beta.-blockers which would be metabolized in one simple, predictable, controllable step to an inactive metabolite which avoiding oxidative metabolism; moreover, the esters of the publications are generally less complex structurally than those described hereinbelow. See also Erhardt et al, J. Med, Chem., 25, 1408-1412 (1982). Similar simple alkyl esters were described much earlier, e.g. Barrett et al U.S. Pat. No. 3,663,607, issued May 16, 1972.